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Tuesday, July 22, 2014

Stress-Induced Mutagenesis and Complex Adaptation

YoavRam, LilachHadany

doi: http://dx.doi.org/10.1101/007096

Abstract:

Because mutations are mostly deleterious, mutation rates should be
reduced by natural selection. However, mutations also provide the raw
material for adaptation. Therefore, evolutionary theory suggests that
the mutation rate must balance between adaptability - the ability to
adapt - and adaptedness - the ability to remain adapted. We model an
asexual population crossing a fitness valley and analyze the rate of
complex adaptation with and without stress-induced mutagenesis - the
increase of mutation rates in response to stress or maladaptation. We
show that stress-induced mutagenesis increases the rate of complex
adaptation without reducing the population mean fitness, thus breaking
the evolutionary trade-off between adaptability and adaptedness. Our
theoretical results support the hypothesis that stress-induced
mutagenesis promotes adaptation and provide quantitative predictions of
the rate of complex adaptation with different mutational strategies.

Wednesday, July 16, 2014

Not strictly cancer but the topic is very relevant to many of us trying to understand the emergence of invasiveness.

The Role of Migration in the Evolution of Phenotypic Switching

OanaCarja, Robert EFurrow, Marc WFeldman

Stochastic switching is an example of phenotypic bet-hedging, where an
individual can switch between different phenotypic states in a
fluctuating environment. Although the evolution of stochastic switching
has been studied when the environment varies temporally, there has been
little theoretical work on the evolution of phenotypic switching under
both spatially and temporally fluctuating selection pressures. Here we
use a population genetic model to explore the interaction of temporal
and spatial variation in the evolutionary dynamics of phenotypic
switching. We find that spatial variation in selection is important;
when selection pressures are similar across space, migration can
decrease the rate of switching, but when selection pressures differ
spatially, increasing migration between demes can facilitate the
evolution of higher rates of switching. These results may help explain
the diverse array of non-genetic contributions to phenotypic variability
and phenotypic inheritance observed in both wild and experimental
populations.

Investigating the development of chemotherapeutic drug resistance in cancer: A multiscale computational study

Chemotherapy is one of the most important therapeutic options used to treat
human cancers, either alone or in combination with radiation therapy and
surgery. Recent studies have indicated that intra-tumoural heterogeneity has a
significant role in driving resistance to chemotherapy in many human
malignancies. Multiple factors including the internal cell-cycle dynamics and
the external microenvironement contribute to the intra-tumoural heterogeneity.
In this paper we present a hybrid, multiscale, individual-based mathematical
model, incorporating internal cell-cycle dynamics and changes in oxygen
concentration, to study the effects of delivery of several different
chemotherapeutic drugs on the heterogeneous subpopulations of cancer cells with
varying cell-cycle dynamics. The computational simulation results from the
multiscale model are in good agreement with available experimental data and
support the hypothesis that slow-cycling sub-populations of tumour cells within
a growing tumour mass can induce drug resistance to chemotherapy and thus the
use of conventional chemotherapy may actually result in the emergence of
dominant, therapy-resistant, slow-cycling subpopulations of tumour cells. Our
results indicate that the appearance of this chemotherapeutic resistance is
mainly due to the inability of the administered drug to target all cancer cells
irrespective of the stage in the cell-cycle they are in i.e. most
chemotherapeutic drugs target cells in a particular phase/phases of the
cell-cycle, and hence always spare some cancer cells that are not in the
targeted cell-cycle phase/phases. The results also suggest that this
cell-cycle-mediated drug resistance may be overcome by using multiple doses of
cell-cycle, phase-specific chemotherapy that targets cells in all phases and
its appropriate sequencing and scheduling.